From Stores to Sinks: Structural Mechanisms of Cytosolic Calcium Regulation

  • Masahiro Enomoto
  • Tadateru Nishikawa
  • Naveed Siddiqui
  • Steve Chung
  • Mitsuhiko IkuraEmail author
  • Peter B. StathopulosEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 981)


All eukaryotic cells have adapted the use of the calcium ion (Ca2+) as a universal signaling element through the evolution of a toolkit of Ca2+ sensor, buffer and effector proteins. Among these toolkit components, integral and peripheral proteins decorate biomembranes and coordinate the movement of Ca2+ between compartments, sense these concentration changes and elicit physiological signals. These changes in compartmentalized Ca2+ levels are not mutually exclusive as signals propagate between compartments. For example, agonist induced surface receptor stimulation can lead to transient increases in cytosolic Ca2+ sourced from endoplasmic reticulum (ER) stores; the decrease in ER luminal Ca2+ can subsequently signal the opening surface channels which permit the movement of Ca2+ from the extracellular space to the cytosol. Remarkably, the minuscule compartments of mitochondria can function as significant cytosolic Ca2+ sinks by taking up Ca2+ in a coordinated manner. In non-excitable cells, inositol 1,4,5 trisphosphate receptors (IP3Rs) on the ER respond to surface receptor stimulation; stromal interaction molecules (STIMs) sense the ER luminal Ca2+ depletion and activate surface Orai1 channels; surface Orai1 channels selectively permit the movement of Ca2+ from the extracellular space to the cytosol; uptake of Ca2+ into the matrix through the mitochondrial Ca2+ uniporter (MCU) further shapes the cytosolic Ca2+ levels. Recent structural elucidations of these key Ca2+ toolkit components have improved our understanding of how they function to orchestrate precise cytosolic Ca2+ levels for specific physiological responses. This chapter reviews the atomic-resolution structures of IP3R, STIM1, Orai1 and MCU elucidated by X-ray crystallography, electron microscopy and NMR and discusses the mechanisms underlying their biological functions in their respective compartments within the cell.


Inositol 1,4,5-trisphosphate receptor (IP3R) Stromal interaction molecule-1 (STIM1) Orai1 Mitochondrial calcium uniporter (MCU) Store operated calcium entry (SOCE) Calcium release activated calcium (CRAC) X-ray crystallography Nuclear magnetic resonance (NMR) spectroscopy Electron microscopy Calcium signaling 



This work was supported by Natural Sciences and Engineering Research Council of Canada (NSERC) 05239 (to P.B.S.), Canadian Institutes of Health Research (CIHR) MOP-13552 (to M.I.), NSERC UT393093 (to M.I.) and an Ontario Graduate Scholarship (to N.S.). M.I. holds the Canada Research Chair in Cancer Structural Biology.


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  • Masahiro Enomoto
    • 1
    • 2
  • Tadateru Nishikawa
    • 1
    • 2
  • Naveed Siddiqui
    • 3
  • Steve Chung
    • 3
  • Mitsuhiko Ikura
    • 1
    • 2
    Email author
  • Peter B. Stathopulos
    • 3
    Email author
  1. 1.Princess Margaret Cancer CenterUniversity Health NetworkTorontoCanada
  2. 2.Department of Medical BiophysicsUniversity of TorontoTorontoCanada
  3. 3.Department of Physiology and PharmacologyUniversity of Western OntarioLondonCanada

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